Skin Problems in Chronic Kidney Disease

Box 1.

Skin Disorders in Patients With Chronic Kidney Disease

Udayakumar P et al. (2006) Cutaneous manifestations in patients with chronic renal failure on hemodialysis. Indian J Dermatol Venereol Leprol 72: 119-125
Abdelbaqi-Salhab M et al. (2003) A current review of the cutaneous manifestations of renal disease. J Cutan Pathol 30: 527-538
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Patel TS et al. (2007) An update on pruritus associated with CKD. Am J Kidney Dis 50: 11-20
Pisoni RL et al. (2006) Pruritus in haemodialysis patients: International results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 21: 3495-3505
Mistik S et al. (2006) An epidemiology study of patients with uremic pruritus. J Eur Acad Dermatol Venereol 20: 672-678
Dyachenko P et al. (2006) Hemodialysis-related pruritus and associated cutaneous manifestations. Int J Dermatol 45: 664-667
Keith-Reddy SR et al. (2007) Uremic pruritus. Kidney Int 72: 373-377
Lin HH et al. (2008) Uremic pruritus, cytokines, and polymethylmethacrylate artificial kidney. Artif Organs 32: 468-472
Narita I et al. (2006) Etiology and prognostic significance of severe uremic pruritus in chronic hemodialysis patients. Kidney Int 69: 1626-1632
Garssen J et al. (1999) UVB exposure-induced systemic modulation of TH1- and TH2-mediated immune responses. Immunology 97: 506-514
Kimmel M et al. (2006) The role of micro-inflammation in the pathogenesis of uremic pruritus in haemodialysis patients. Nephrol Dial Transplant 21: 749-755
Qureshi AR et al. (2002) Inflammation, malnutrition, and cardiac disease as predictors of mortality in hemodialysis patients. J Am Soc Nephrol 13 (Suppl): S28.S36
Umueuchi H et al. (2003) Involvement of central µ-opioid system in the scratching behavior in mice, and the suppression of itch by the activation of µ-opioid system. Eur J Pharmacol 477: 29-35
Kumagai H et al. (2004) Prospects for a novel kappaopioid receptor agonist, TRK-820, in uremic pruritus. In Itch, Basic Mechanisms and Therapy, 279-286 (Eds Yosipovitch G et al.) New York, NY: Dekker
Wikstrom B et al. (2005) Kappa-opioid system in uremic pruritus: multicenter, randomized, doubleblind, placebo-controlled clinical studies. J Am Soc Nephrol 16: 3742-3747
Peer G et al. (1996) Randomised cross-over-trial of naltrexone in uraemic pruritus. Lancet 348: 1552-1554
Cho YL et al. (1997) Uremic pruritus: roles of parathyroid hormone and substance P. J Am Acad Dermatol 36: 538-543
Chou FF et al. (2000) A study on pruritus after parathyroidectomy for secondary hyperparathyroidism. J Am Coll Surg 190: 65-70
Momose A et al. (2004) Calciums ions are abnormally distributed in the skin of haemodialysis patients with uraemic pruritus. Nephrol Dial Transplant 19: 2061-2066
Szepietowski J et al. (1995) Pruritus and mast cell proliferation in the skin of haemodialysis patients. Inflamm Res 44 (Suppl 1): S84.S85
Dugas-Breit S et al. (2005) Baseline serum levels of mast cell tryptase are raised in hemodialysis patients and associated with severity of pruritus. J Dtsch Dermatol Ges 3: 343-347
Balaskas EV et al. (1998) Histamine and serotonin in uremic pruritus: effect of ondansetron in CAPDpruritic patients. Nephron 78: 395-402
Ashmore SD et al. (2000) Ondansetron therapy for uremic pruritus in hemodialysis patients. Am J Kidney Dis 35: 827-831
Fantini F et al. (1992) Cutaneous innervation in chronic renal failure patients: an immunohistochemical study. Acta Derm Venereol 72: 102-105
Johansson O et al. (1989) Intra-epidermal neuronspecific enolase (NSE)-immunoreactive nerve fibres: evidence for sprouting in uremic patients on maintenance hemodialysis. Neurosci Lett 99: 281-286
Morton CA et al. (1996) Pruritus and skin hydration during dialysis. Nephrol Dial Transplant 11: 2031-2036
Okada K et al. (2004) Effect of skin care with an emollient containing a high water content on mild uremic pruritus. Ther Apher Dial 8: 419-422
Chen YC et al. (2006) Therapeutic effect of topical gamma-linolenic acid on refractory uremic pruritus. Am J Kidney Dis 48: 69-76
Wasik F et al. (1996) Relief of uraemic pruritus after balneological therapy with a bath oil containing polidocanol (Balneum Hernal Plus): an open clinical study. J Dermatol Treat 7: 231-233
Szepietowski JC et al. (2005) Efficacy and tolerance of the cream containing structured physiological lipids with endocannabinoids in the treatment of uremic pruritus: a preliminary study. Acta Dermatovenerol Croat 13: 97-103
Breneman DL et al. (1992) Topical capsaicin for the treatment of hemodialysis-related pruritus. Am Acad Dermatol 26: 91-94
Tarng DC et al. (1996) Hemodialysis-related pruritus: a double-blind, placebo-controlled, cross-over study of capsaicin 0.025% cream. Nephron 72: 617-622
Kuypers DK et al. (2004) A prospective proof of concept study of the efficacy of tacrolimus ointment on uremic pruritus (UP) in patients on chronic dialysis therapy. Nephrol Dial Transplant 19: 1895-1901
Duque MI et al. (2005) Lack of efficacy of tacrolimus ointment 0.1% for treatment of hemodialysis-related pruritus: a randomized, double-blind, vehiclecontrolled study. J Am Acad Dermatol 52: 519-521
US Food and Drug Administration (online 10 March 2005) FDA Public Health Advisory: Elidel (pimecrolimus) cream and Protopic (tacrolimus) ointment. [www.fda.gov/medwatch/SAFETY/2005/safety05.htm#Elidel] (accessed 2 January 2009)
Naylor M et al. (2005) Non-melanoma skin cancer in patients with atopic dermatitis treated with topical tacrolimus. J Dermatolog Treat 16: 149-153
Munzenberger PJ et al. (2007) Safety of topical calcineurin inhibitors for the treatment of atopic dermatitis. Pharmacotherapy 27: 1020-1028
Gilchrest BA et al. (1979) Ultraviolet phototherapy of uremic pruritus. Long-term results and possible mechanism of action. Ann Intern Med 91: 17-21
Ada S et al. (2005) Treatment of uremic pruritus with narrowband ultraviolet B phototherapy: an open pilot study. J Am Acad Dermatol 53: 149-151
Seckin D et al. (2007) Generalized pruritus treated with narrowband UVB. Int J Dermatol 46: 367-370
Gunal AI et al. (2004) Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebocontrolled, double-blind trial. Nephrol Dial Transplant 19: 3137-3139
Manenti L et al. (2005) Gabapentin in the treatment of uremic itch: an index case and pilot evaluation. J Nephrol 18: 86-91
Pauli-Magnus C et al. (2000) Naltrexone does not relieve uremic pruritus: results of a randomized, double-blind, placebo-controlled crossover study. J Am Soc Nephrol 11: 514-519
Imaizumi A et al. (2003) Effective treatment of pruritus on atopic dermatitis using H1 antihistamines (second-generation antihistamines): changes in blood histamine and tryptase levels. J Dermatol Sci 33: 23-29
Pederson JA et al. (1980) Relief of idiopatic generalized pruritus in dialysis patients treated with activated oral charcoal. Ann Intern Med 93: 446-448
Giovannetti S et al. (1995) Oral activated charcoal in patients with uremic pruritus. Nephron 70: 193-196
Layegh P et al. (2007) Effect of oral granisetron in uremic pruritus. Indian J Dermatol Venereol Leprol 73: 231-234
Silva SR et al. (1994) Thalidomide for the treatment of uremic pruritus: a crossover randomized doubleblind trial. Nephron 67: 270-273
De Marchi S et al. (1992) Relief of pruritus and decreases in plasma histamine concentrations during erythropoietin therapy in patients with uremia. N Engl J Med 326: 969-974
Janigan DT et al. (2000) Calcified subcutaneous arterioles with infarcts of the subcutis and skin ('calciphylaxis') in chronic renal failure. Am J Kidney Dis 35: 588-597
Wilmer W et al. (2002) Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial 15: 172-186
Weenig RH et al. (2007) Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol 56: 569-579
Rogers NM et al. (2007) Calcific uremic arteriolopathy: advances in pathogenesis and treatment. Semin Dial 20: 150-157
Mazhar AR et al. (2001) Risk factors and mortality associated with calciphylaxis in end-stage renal disease. Kidney Int 60: 324-332
Essary LR et al. (2000) Cutaneous calciphylaxis: an underrecognized clinicopathologic entity. Am J Clin Pathol 113: 280-287
Bleibel W et al. (2006) A case report comparing various radiological tests in the diagnosis of calcific uremic arteriolopathy. Am J Kidney Dis 48: 659-661
Wilmer WA et al. (2001) Transcutaneous oxygen tension in patients with calciphylaxis. Am J Kidney Dis 37: 797-806
Soni S et al. (2008) Bone scan findings in metastatic calcification from calciphylaxis. Clin Nucl Med 33: 502-504
Shroff RX et al. (2007) The vascular biology of calcification. Semin Dial 20: 103-109
Weenig RH (2008) Pathogenesis of calciphylaxis: Hans Selye to nuclear factor κB. J Am Acad Dermatol 58: 458-471
Moe SM et al. (2003) Calciphylaxis and vascular calcification: a continuum of extra-skeletal osteogenesis. Pediatr Nephrol 18: 969-975
Griethe W et al. (2003) Bone morphogenic protein-4 expression in vascular lesions of calciphylaxis. J Nephrol 16: 728-732
Ahmed S et al. (2001) Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells. Am J Kidney Dis 37: 1267-1276
Vattikuti R et al. (2004) Osteogenic regulation of vascular calcification: an early perspective. Am J Physiol Endocrinol Metab 286: E686-E696
Schafer C et al. (2003) The serum protein α2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopy calcification. J Clin Invest 112: 357-366
Cranenburg EC et al. (2008) The circulating inactive form of Matrix Gla Protein (ucMGP) as a biomarker for cardiovascular calcification. J Vasc Res 45: 427-436
Chen NX et al. (2006) Uremic vascular calcifications. J Investig Med 54: 380-384
Girotto JA et al. (2001) Parathyroidectomy promotes wound healing and prolongs survival in patients with calciphylaxis from secondary hyperparathyroidism. Surgery 130: 645-651
Galimberti RL et al. (2005) Cutaneous necrosis by calcific uremic arteriolopathy. Int J Dermatol 44: 101-106
Velasco N et al. (2006) Successful treatment of calciphylaxis with cinacalcet—an alternative to parathyroidectomy? Nephrol Dial Transplant 21: 1999-2004
Guerra G et al. (2005) Rapid resolution of calciphylaxis with intravenous sodium thiosulfate and continuous venovenous haemofiltration using low calcium replacement fluid: case report. Nephrol Dial Transplant 20: 1260-1262
Meissner M et al. (2007) Sodium thiosulfate: a new way of treatment for calciphylaxis? Dermatology 214: 278-282
Mataic D et al. (2006) Intraperitoneal sodium thiosulfate for the treatment of calciphylaxis. Ren Fail 28: 361-363
Shiraishi N et al. (2006) Successful treatment of a patient with severe calcific uremic arteriolopathy (calciphylaxis) by etidronate sodium. Am J Kidney Dis 48: 151-154
da Costa JB et al. (2007) Pamidronate as a treatment option in calciphylaxis. J Eur Acad Dermatol Venereol [doi:10.1111/j.1468-3083.2007.02532.x]
Hanafusa T et al. (2007) Intractable wounds caused by calcific uremic arteriolopathy treated with bisphosphonates. J Am Acad Dermatol 57: 1021-1025
Basile C et al. (2002) Hyperbaric oxygen therapy for calcific uremic arteriolopathy: a case series. J Nephrol 15: 676-680
Mendoza FA et al. (2006) Description of twelve cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum 35: 238-249
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DeHoratius DM et al. (2006) Nephrogenic systemic fibrosis: an emerging threat among renal patients. Semin Dial 19: 191-194
Evenepoel P et al. (2004) Nephrogenic fibrosing dermopathy: a novel, disabling disorder in patients with renal failure. Nephrol Dial Transplant 19: 469-473
Fazeli A et al. (2004) Nephrogenic fibrosing dermopathy: are ACE inhibitors the missing link? Arch Dermatol 140: 1401
Wiginton CD et al. (2008) Gadolinium-based contrast exposure, nephrogenic systemic fibrosis, and gadolinium detection in tissue. AJR Am J Roentgenol 190: 1060-1068
Swaminathan S et al. (2006) Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Ann Intern Med 145: 234-235
Broome DR (2008) Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting. Eur J Radiol 66: 230-234
Perazella MA (2007) Nephrogenic systemic fibrosis, kidney disease and gadolinium: is there a link? Clin J Am Soc Nephrol 2: 200-202
Perazella MA et al. (2007) Gadolinium use in patients with kidney disease: a cause for concern. Semin Dial 20: 179-184
Khurana A et al. (2008) Quantification of gadolinium in nephrogenic systemic fibrosis: re-examination of a reported cohort with analysis of clinical factors. J Am Acad Dermatol 59: 218-224
Kucher C et al. (2005) Histopathologic comparison of nephrogenic fibrosing dermopathy and scleromyxedema. J Cutan Pathol 32: 484-490
Digby S et al. (2008) Nephrogenic systemic fibrosis: a histopathological study of eight cases of a recently described entity. Histopathology 52: 531-534
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Abraham JL et al. (2008) Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis. Br J Dermatol 158: 273-280
Edward M et al. (2007) Cutaneous mucinosis associated with dermatomyositis and nephrogenic fibrosing dermopathy: fibroblast hyaluronan synthesis and the effect of patient serum. Br J Dermatol 156: 473-479
Edward M et al. (2008) Gadodiamide contrast agent 'activates' fibroblasts: a possible cause of nephrogenic systemic fibrosis. J Pathol 214: 584-593
Kelly B et al. (2008) Nephrogenic systemic fibrosis is associated with transforming growth factor β and Smad without evidence of renin-angiotensin system involvement. J Am Acad Dermatol 58: 1025-1030
Schroeder JA et al. (2008) Ultrastructural evidence of dermal gadolinium deposits in a patient with nephrogenic systemic fibrosis and endstage renal disease. Clin J Am Soc Nephrol 3: 968-975
High WA et al. (2007) Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 56: 21-26
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Thakral C et al. (2007) Automated scanning electron microscopy and X-ray microanalysis for in situ quantification of gadolinium deposits in skin. J Electron Microsc (Tokyo) 56: 181-187
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Summary and Introduction

Summary

Skin disorders associated with chronic kidney disease (CKD) can markedly affect a patient's quality of life and can negatively impact their mental and physical health. Uremic pruritus, which is frequently encountered in patients with CKD, is considered to be an inflammatory systemic disease rather than a local skin disorder. Biomarkers of inflammation are increased in patients with uremic pruritus and an imbalance of the endogenous opioidergic system might be involved in the complex pathogenesis of the disease. Treatment options for uremic pruritus include emollients, topical capsaicin cream, ultraviolet B phototherapy, gabapentin, oral activated charcoal and nalfurafine, a κ-opioid-receptor agonist. Calcific uremic arteriolopathy is triggered by an imbalance of promoters and inhibitors of vascular calcification, caused by the inflammatory changes that occur in uremia. Promising therapeutic strategies for calcific uremic arteriolopathy include bisphosphonates and intravenous sodium thiosulfate. Nephrogenic systemic fibrosis is a devastating condition associated with the use of gadolinium-based contrast agents in patients with CKD. At present, no therapies are available for this complication. Preventive measures include use of iodine-based contrast agents, particularly in patients with CKD stage 4 and 5. If gadolinium contrast is necessary, administration of low volumes of the more stable macrocyclic ionic types of gadolinium-based contrast agent is advocated. Hemodialysis following gadolinium exposure might offer benefits but evidence is lacking.

Introduction

A wide variety of skin diseases occur in patients with chronic kidney disease (CKD; Box 1 ).^[1-3] These diseases are sometimes related to the underlying renal illness but are more frequently directly or indirectly associated with 'uremia' in its broadest sense. With an almost 100% prevalence in dialysis populations, skin disorders are frequently the subject of patients' complaints.^[1] A basic knowledge of the dermatological conditions that can arise in the setting of kidney disease is, therefore, very useful to practicing nephrologists. Skin diseases have a considerable negative effect on a patient's quality of life. They can induce serious discomfort, anxiety, depression and sleeping disorders and have an overall negative effect on mental and physical health. Although the majority of dermatological disorders in CKD are relatively benign, a few rare skin diseases have the potential to cause serious morbidity and mortality. Early recognition of these severe skin disorders and prompt initiation of treatment can dramatically alter their course and even save a patient's life. In this Review we discuss uremic pruritus (UP), an ongoing therapeutic challenge in patients with CKD. In addition, we discuss calcific uremic arteriolopathy (CUA) and nephrogenic systemic fibrosis (NSF), which are potentially dangerous skin diseases that require prompt clinical identification and treatment. Finally, acquired perforating dermatosis (Kyrle disease) and porphyria cutanea tarda are briefly described.